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Research Description

Transcriptional regulation of gene expression:

Regulation of
gene expression by transcription factors (TFs) is pivotal for determining cell
fate during development and normal homeostasis, and de-regulation of gene
transcription contribute to many diseases. The homeodomain TFs, POU4F1/Brn-3a (Brn-3a) and related POU4F2/Brn-3b, (Brn-3b),
are distinct but related regulators that share high homology in the DNA binding
POU domain but differ considerably in other regions. As such, Brn-3a and Brn-3b
bind to similar DNA sequences in the promoters of target genes but can give
rise to diverse effects on gene expression/cell fate.

However, the effects of
these transcription factors are highly dependent on the tissue of expression
and growth conditions as well as co-expression with other regulators such as
p53. For example, Brn-3a enhances neuronal differentiation by activating synaptic
protein SNAP25, neurofilament (NFH); a-internexin etc. and survival
by increasing anti-apoptotic Bcl-2 or BclXL
whilst repressing p53 mediated pro-apoptotic target genes (Bax and Noxa). In
contrast, Brn-3b drives proliferation by activating cell cycle
proteins, cyclin D1 and CDK4 but if co-expressed with p53, brn-3b cooperates
with p53 to enhance Bax expression and hence apoptosis.

These findings have demonstrated
how co-expression of different TFs can influence cell fate. Furthermore the
cooperation between Brn-3b and p53 to promote apoptosis may support a novel
paradigm for understanding how cells respond to conflicting signals arising
from co-expression of Brn-3b which normally stimulates cell proliferation, and
p53, which drives cell cycle arrest. Given their
complex effects on cell fate, it is necessary to analyse the effects of Brn-3a
and Brn-3b in cell/tissue specific context and determine how co-expression with
other cellular factors can affect gene expression and cell fate.

Although
Brn-3a and Brn-3b have been studied extensively in neuronal cells and retinal
ganglion cells, respectively, these TF are expressed in other tissues/system such
as the heart and are deregulated in diseases such as cancers. Our primary research
in MMBU has focused on studying how transcriptional regulators such as Brn-3a
and Brn-3b act in different tissues under normal conditions and identify
changes that may contribute to diseases.

(2001). The closely related POU family transcription factors Brn-3a and Brn-3b are expressed in distinct cell types in the testis. The International Journal of Biochemistry and Cell Biology, 33(10), 1027 - 1039.